The novel process is particularly useful for the preparation of an intermediate in the synthesis of the protease inhibitor, indinavir sulfate (CRIXIVAN.RTM.) which is known to be useful in the prevention of infection by HIV (human immunodeficiency virus), the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS).
Previously, the synthesis of indinavir and related compounds was accomplished via a 12-step procedure which employed a hydroxy protected dihydro-5(S)-hydroxymethyl-3(2H) furanone which was alkylated, and involved replacement of an alcohol leaving group on the alkylated furanone with a piperidine moiety. The coupled product was then hydrolyzed to open the furanone ring into a hydroxy acid moiety, and the acid was ultimately coupled to 2(R)-hydroxy-1(S)-aminoindane. This procedure is described in U.S. Pat. No.5,413,999. The extreme length of this route (12 steps), renders this process time consuming and labor intensive, and it requires the use of many expensive reagents and an expensive starting material. A route requiring fewer reaction steps and reagents would provide desirable economical and time-saving benefits.
A modified route to indinavir and related compounds was also shown in U.S. Pat. No. 5,413,999 based on the diastereoselective alkylation of the enolate derived from N-(2(R)-hydroxy-1(S)-indan-N,O-isopropylidenyl) -3-phenyl-propaneamide, in which the C.sub.3 -C.sub.5 three-carbon unit was introduced as an allyl group and later oxidized. Some problems with this route are: (a) four steps are necessary to effect the introduction of the three carbon glycidyl fragment, (b) highly toxic OsO.sub.4 is used in the process and (c) low diastereoselectivity is obtained in the dihydroxylation step. Thus, a desirable process would directly introduce the three carbon unit in the correct chiral oxidized form.
Furthermore, the synthesis of the chiral piperazine intermediate was effected from 2-pyrazinecarboxylic acid in a 6 step procedure and required the use of expensive reagents such as BOC-ON and EDC. A shorter route to the piperazine intermediate which also does not use expensive reagents would thus be desired. Moreover, during the synthesis of the chiral piperazine intermediate, both the desired (S)-piperazine carboxylate enantiomer (i.e., the precursor to the 2(S)-carboxamide piperazine intermediates) and the undesired (R)-enantiomer are formed requiring separation of the desired (S)-enantiomer which is then carried on to ultimately form indinavir. In the absence of practical methodology for converting the (R)-antipode to the (S)-antipode, it was discarded as waste, thus limiting the possible efficiency of this step to 50%.
More recently, a shorter route for preparing the compounds disclosed in U.S. Pat. No. 5,413,999 and in particular indinavir, was found. In this newer route, 1-((R)-2',3'-Epoxypropyl-(S)-2-tert-butylcarbonyl-piperazine is prepared and reacted with N-(2(R)-hydroxy-1(S)-indan-N,O-isopropylidene-yl) -3-phenylpropaneamide to give the coupled product. ##STR2##
After removal of the BOC protecting group from the piperazine nitrogen, the unprotected piperazine compound is then reacted with 3-picolyl chloride to form indinavir.
Still more recently, a novel process somewhat similar to the presently claimed process for preparing the same intermediate as in the present process was claimed in WO 95/23797. That process is as follows: ##STR3##
In that process N-chlorosuccinimide (NCS) is used as the oxidant for iodohydrination of allyl acetonide intermediate I. With the present invention, NaOCl is used as the oxidant which has several advantages. First of all, NaOCl is a much less expensive raw material as compared with NCS. Secondly, NCS is a sticky solid which is difficult to handle effectively in the manufacturing process. On the other hand, NaOCl (aqueous) is a solution which can be easily handled by a liquid pump. Thirdly, a large amount of succinimide is present in the waste aqueous stream in the NCS process, which would hinder the recovery of iodide from the waste stream. The NaOCl process of the present invention eliminates succinimide as a side product, hence facilitating the recovery of iodide from the waste stream.
Halohydrination of Compound I can also be accomplished electrochemically by passing a current through a solvent system containing the substrate, I, and sodium iodide or sodium bromide, using carbon felt as electrodes (Tetrahedron Lett. 1997, 38, 777). Using a biphasic solvent system of isopropyl acetate/water, the iodohydrin can be produced, but with a low yield of 69%. Using acetonitrile/water as solvent, the bromohydrin can be produced with 86% yield and a relatively low diastereoselectivity of 88%de.
The novel process of the present invention is clearly superior to other known processes for the preparation of the halohydrin product by virtue of higher physical yields, greater diastereoselectivity and/or ease of isolation and waste disposal.